Autophagy in Antiviral Immunity

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Title: Autophagy in Antiviral Immunity
Author: Orvedahl, Anthony Walter
Abstract: Autophagy is an evolutionarily conserved pathway in which cytoplasmic material is sequestered in a double -membrane vesicle and delivered to the lysosome for degradation . During times of stress , autophagy functions to generate essential nutrients through the degradation of non -essential cytoplasmic contents . It is also the only known mechanism for removal of damaged or superfluous organelles and cytoplasmic contents that are too large to be degraded by the proteasome . Given the critical role for autophagy in stress response and in maintaining cell cytoplasmic quality control , it is not surprising that autophagy plays an essential role in the host response to infection , and that microbes have evolved mechanisms to counteract or evade autophagy . In this work , we studied the role of autophagy inhibition in a mouse model of herpes simplex virus type I (HSV -1 ) encephalitis , investigated the role of autophagy in protection against Sindbis virus infection of the central nervous system , and identified novel host genes involved in targeting viral proteins to the autophagy pathway . We found that the HSV -1 encoded neurovirulence protein ICP34 .5 interacted with the host autophagy protein Beclin 1 , and that this interaction was essential for HSV -1 neurovirulence . This was the first example of a viral virulence protein that targets host autophagy , and provided evidence that autophagy functions in innate immunity to viruses . In the second study , we found that the host autophagy gene Atg5 was required to protect against lethal Sindbis virus CNS diseases , and that autophagy targeted viral proteins for degradation in brains of infected mice and cells in vitro . We found that the autophagy adaptor protein p62 was involved in targeting viral proteins for autophagic degradation and this promoted survival of infected cells . This study demonstrated that clearance of viral proteins by autophagy was an important mechanism for cellular and organismal survival during viral infection . Lastly , we performed a genome -wide siRNA screen to identify novel host factors required for autophagic targeting of viral proteins . We identified previously unappreciated cellular networks and genes that were involved in targeting viral proteins for autophagy . One of these factors , SMURF1 , is an E3 ubiquitin ligase that not only functions to target viral proteins , but is also involved in targeting damaged mitochondria for autophagic clearance . [Keywords : autophagy ; innate immunity ; virus ; infection ; Herpes Simplex Virus Tupe I (HSV -1 ) ; Sindbis virus ; mitophagy ; central nervous system (CNS ) ; pb2 /SQSTM1 ; SMURF1]
URI: http : / /hdl .handle .net /2152 .5 /1111
Date: 2012-08-15


Autophagy in Antiviral Immunity. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /1111 .

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